Role of the mitochondrial Ca2+ uniporter in Pb2+-induced oxidative stress in human neuroblastoma cells

Abstract Lead (Pb 2+ ) has been shown to induce cellular oxidative stress, which is linked to changes in intracellular calcium (Ca 2+ ) concentration. The mitochondrial Ca 2+ uniporter (MCU) participates in the maintenance of Ca 2+ homeostasis in neurons, but its role in Pb 2+ -induced oxidative stress is unclear. To address this question, oxidative stress was induced in human neuroblastoma SH-SY5Y cells and in newborn rats by Pb 2+ treatment. The results showed that the production of reactive oxygen species is increased in cells upon treatment with Pb 2+ in a dose-dependent manner, while glutathione and MCU expression were reduced. Moreover, neuronal nitric oxide synthase protein expression was elevated in rats exposed to Pb 2+ during gestation, while MCU expression was decreased. Application of the MCU activator spermine or MCU overexpression reversed Pb 2+ -induced oxidative stress and inhibition of mitochondrial Ca 2+ uptake, while the MCU inhibitor Ru360 and MCU knockdown potentiated the effects of Pb 2+ . These results indicate that the MCU mediates the Pb 2+ -induced oxidative stress response in neurons through the regulation of mitochondrial Ca 2+ influx.